Lgr4 Protein Deficiency Induces Ataxia-like Phenotype in Mice and Impairs Long Term Depression at Cerebellar Parallel Fiber-Purkinje Cell Synapses
Lgr4 Protein Deficiency Induces Ataxia-like Phenotype in Mice and Impairs Long Term Depression at Cerebellar Parallel Fiber-Purkinje Cell Synapses
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Lgr4 蛋白缺乏会诱导小鼠出现共济失调样表型，并损害小脑平行纤维浦肯野细胞突触的长期抑制
DOI：
10.1074/jbc.m114.564138
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发表时间：
2014-09-19
影响因子：
4.8
通讯作者：
Liu, Mingyao
中科院分区：
文献类型：
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作者：
Guan, Xin;Duan, Yanhong;Liu, Mingyao
小脑功能障碍导致共济失调，其特征是失去平衡和协调。迄今为止，几种遗传性小脑共济失调的分子和神经机制尚未完全阐明。在这里，我们报道富含亮氨酸的 G 蛋白偶联受体 4 (Lgr4/Gpr48) 在小脑的浦肯野细胞 (PC) 中高度表达。 Lgr4 缺乏会导致小鼠出现共济失调样表型。组织学上，Lgr4突变小鼠小脑未观察到明显的形态学变化。然而，Lgr4(-/-) 小鼠中 PC 的数量略有但显着减少。此外，体外电生理学分析显示 Lgr4(-/-) 小鼠平行纤维 PC (PF-PC) 突触的长期抑制 (LTD) 受损。一致地，免疫染色实验表明Lgr4(-/-) PC中磷酸化cAMP反应元件结合蛋白(Creb)的水平显着降低。此外，用毛喉素（一种腺苷酸环化酶激动剂）治疗，可挽救 PC 中的磷酸化 Creb，并逆转 Lgr4(-/-) 小脑切片中 PF-PC LTD 的损伤，表明 Lgr4 是 Creb 信号传导的上游调节因子，而 Creb 信号传导是 PF-PC LTD 的基础。总之，我们的研究结果首次证明了 Lgr4 在运动协调和小脑突触可塑性中的重要作用，并为某些类型的遗传性小脑共济失调提供了潜在的治疗靶点。
Cerebellar dysfunction causes ataxia characterized by loss of balance and coordination. Until now, the molecular and neuronal mechanisms of several types of inherited cerebellar ataxia have not been completely clarified. Here, we report that leucine-rich G protein-coupled receptor 4 (Lgr4/Gpr48) is highly expressed in Purkinje cells (PCs) in the cerebellum. Deficiency of Lgr4 leads to an ataxia-like phenotype in mice. Histologically, no obvious morphological changes were observed in the cerebellum of Lgr4 mutant mice. However, the number of PCs was slightly but significantly reduced in Lgr4(-/-) mice. In addition, in vitro electrophysiological analysis showed an impaired long term depression (LTD) at parallel fiber-PC (PF-PC) synapses in Lgr4(-/-) mice. Consistently, immunostaining experiments showed that the level of phosphorylated cAMP-responsive element-binding protein (Creb) was significantly decreased in Lgr4(-/-) PCs. Furthermore, treatment with forskolin, an adenylyl cyclase agonist, rescued phospho-Creb in PCs and reversed the impairment in PF-PC LTD in Lgr4(-/-) cerebellar slices, indicating that Lgr4 is an upstream regulator of Creb signaling, which is underlying PF-PC LTD. Together, our findings demonstrate for first time an important role for Lgr4 in motor coordination and cerebellar synaptic plasticity and provide a potential therapeutic target for certain types of inherited cerebellar ataxia.